Derivatives of 3, 6-disubstituted-7-sulfamylbenzothiadiazine dioxides



United States Patent 3,110,716 DERIVATIVES 0F 3,6-DISUBSTlTU'I'ED-7-SULF- AMYLBENZOTHIADIAZINE DEOXIDES William M. McLamore, Kew Gardens, and Gerald D.

Laubach, Jackson Heights, N.Y., assignors to Chas.

Pfizer & Co., Inc., New York, N.Y., a corporation of Delaware No Drawing. Filed Feb. 17, 1958, Ser. No. 715,482

6 Claims. (Cl. 260243) This invention is concerned with a new class of highly efiective therapeutic agents as well as the method of preparing same. In particular, the therapeutic agents of this invention are 3,6-disubstituted-7-sulfamylbenzo-1,1- dioxo-1-thia-2,4-diazines which have proved to be valuable diuretic agents. These compounds, hereinafter referred to as 3,6-disubstituted-7-sulfamylbenzothiadiazine dioxides, are represented by the following formulae:

wherein (a) A is selected from the group consisting of 01, F, Br, N0 alkanoyl containing 2 to 4 carbon atoms, trifluoromethyl, and alkyl and alkoxy each containing from 1 to 3 carbon atoms;

(b) R and R are selected from the group consisting of hydrogen, lalldy containing from 1 to 3 carbon atoms, phenyl, and alkaryl and aralkyl each containing from 7 to 8 carbon atoms;

(c) Y is selected from the group consisting of piperidino, pyrryl, pyrrolidino and morpholino and in whiclR and R are as defined above and (d) Z is selected from the group consisting of pyridinium, pyrirnidinium, thiazolium, pyrazinium, N-alkylpiperidino, N-aikylpyrryl, N-alkylpyrrolidino and N-alkylmorpholino, the N-alkyl of each containing 1 to 3 carbon atoms and in which R and R are as defined above and R is alkyl containing 1 to 3 carbon atoms.

Although in the above formulae reference is made to a preferred carbon content of the described alkanoyl and hydrocarbon substituents, 3,6-disubstituted-7-sulfamylbenzothiadiazine dioxide containing similar groups with higher carbon content may be employed. However, the therapeutic activity of such compounds may tend to decrease. Further, since 3,6-disubstituted-7-sulfamylbenzothiadiazine dioxide containing alk-anoyl and hydrocarbon substituen-ts of higher carbon content provide no appre ciable advantage and the starting compounds for the production of said compounds are generally less economically advisable, they are not preferred.

It is also intended to include within the scope of this invention the acid and base addition salts of the above 3,110,716 Patented Nov. 12, 1963 "ice wherein R and R are as described above are compounds such as:

3-(Z-N-methylamino-Z-propyl)-6-nitro-7 sulfamylbenzothiadiazine dioxide;

3-(a-N-propylamino-a-phenylethyl)-6-propoxy 7-sulfamylbenzothiadiazine dioxide;

3-(ct-N-ianilinO-oc-butyl)6-Chl0l'0 7-sulfamylbenzothiadiazine dioxide;

3-( -N-o. toluidino-y-phenyipropyl)-6-propyl-7-sulfamylbenzothiadiazine dioxide;

3 (N ethyl, N-methylamino). (diphenyl)methyl-6- chloro-7-sulfarnylbenzothiadiazine dioxide;

3 (0c N,N -dipropylamino-ot-p-methylbenzyl-6-bromo-7- suifamylbenzothiadiazine dioxide;

3-(cz N,N dimethylamino-ot-p-ethylbenzyl)-6-bromo-7- sulfamylbenzothiadiazine oxide;

3-(N-benzylaminomethyl) 6-chlor0-7-sulfamy1benzothiiadiazine dioxide;

3-(2 phenylethylamino-2-propyl)-6-nitro-7-sulfamylbenzothiadiazine dioxide;

3-(a-N-p-toiuidino-ot-ethyl)-6-methoxy 7 sulfamylbenzothiadiazine dioxide;

3 (N-methy1anilinomethyl) 6-methyl-7-sulfamylbenzothiadiazine dioxide; 3-(aminomethyl)-6-chloro-7 sulfamy lbenzothiadi-azine dioxide;

3-(2-amino-2-propyl) 6 bromo-7-suifamylbenzothiadiazine dioxide;

3 (1 amino 1 butyl) -6-chioro-7-su1famylbenzothiadiazine dioxide;

3-(a-aminobenzyl) -6-chloro 7 sulfamylbenzothiadiazine dioxide;

3-(2-amino-2-propyl)-6-fiuoro-7-sulfamylbenzothiadiazine dioxide;

3-(l-amino-l-butyl)-6-acetyl-7 sulfamylbenzothiadiazine dioxide;

3-(aminomethyl) 6 trifluoromethyl-7-sulfiamylbenzothi- :adiazine dioxide;

3-(amino-methyl)-6-butyryl-7 sulfamylbenzothiadiazine dioxide;

3-(2-amino 2 propyl) 6 acetyl-7-sulfamylbenzothiadiazine dioxide.

Examplary of compounds in which Y is a heterocyclic radical as described above are compounds such as 3-(N-piperidinomethyl) 6 chioro 7 sulfamylbenzothiadiazine dioxide;

3 (N pyrrylmethyl) 6 ch1oro-7-sulfamylbenzothiadiazine dioxide;

B-(N-piperidinomethyl) -6-methyl-7 sulfamylbenzothiadiazine dioxide;

3 (u N-pyrrolidino-u-ethyl)-6-methoxy-7-sulfamylbenzothiadiazine dioxide;

3-(a-N-morpholino-a-benzyl)-6-methy1-7 sulfamylbenzothiadiazine dioxide;

3-(a-N-piperidino-u-ethyl) 6 methoxy-7-sulfamylbenzothiadiazine dioxide;

3 (2-N-piperidino-2-propyl)-6-nitro-7-sulfamylbenzothiadiazine dioxide;

3-(a-N-pyrrolidino-a-phenylethyl) -6-propoxy-7 sulfarnylbenzothiadiazine dioxide;

3-(N-piperidinomethy1) 6-fluoro-7-su1famylbenzothiadi zine dioxide;

3 3-(2-N-pyrryl-2 propyl)-6-iluoro-7-sulfamylbenzothiadiazine dioxide. The therapeutic agents of this invention in which Z is a heterocyclic radical, an N-alkylheterocyclic radical or R1 N Rr as described above may be represented by the following This formula is a quaternary ammonium zWitter-ion formula. A zwitter-ion is a complex ion that is both positively and negatively charged. The negative charge in this formula resides on the imide nitrogen of the thiadiazine ring. The positive charge resides on the nitrogen atom of group Z.

The benzothiadiazine dioxides in which Z is a heterocyclic radical are exemplified by the following, which are zwitter-ions:

3-(N-pyridiniummethyl)-6-chloro-7-sulfamylbenzothiadiazine dioxide;

3-(N-pyraziniummethyl)-6-bromo-7-sulfamylbenzothiadiazine dioxide;

3-(N-pyridiniumethyl)-6-methyl-7-sulfamylbenzothiadiazine dioxide;

3- l-N-thiazolium-l-ethyl -6-methoxy-7-sulfamylbenzothiadiazine dioxide;

3-( Z-N-pyridiniurn-Z-propyl -6-nitro-7-sulfamylbenzothiadiazine dioxide;

3- a-N-thiazo-liu -a-phenylethyl) -6-pr0poxy-7-sulfamy1- benzothiadiazine dioxide;

3- N-pyrimidiniummethyl -6-bromo-7-sulfamylbenzothiadiazine dioxide;

3 a-N-pyridinium-a-phenylethyl -6-propoxy-7-sul famylbenzothiadiazine dioxide;

3- (N-thiazoliummethyl) -6-chloro-7-sul-famy1benzothiadiazine dioxide;

3 (-N-p yridiniummethyl) -6-fiuoro-7-sulfamylbenzo thiadiazine dioxide;

3 N-pyridinium-methyl -6-trifiuorome-thyl-7-sulfamylbenzothiadiazine dioxide and so forth.

3-( a-Nethylpyrrolidino-a-phenylethyl) -6-propoxy-7- sulfamylbenzothiadiazine dioxide;

3-( a-N,N-dimethyl p-toluidino-a-ethyl -6-methoxy-7- sulfarnylbenzothiadiazine dioxide;

3- N,N-diethyl, N-benzy laminornethyl)-6-chloro-7- sulfamylbenzothi-adiazine dioxide;

3- a-N,N-dirnethylanilino-:x-butyl -6-chloro-7-sulfamylbenzothiadiazine dioxide;

3-( N- methylpiperidinomethyl -6-fluoro-7-sulfamylbenzothiadiazine dioxide;

3-( 2-Nmethylpyrryl-2-propyl) -6-fluoro-7-sulfamy1- thiadiazine dioxide.

The valuable therapeutic agents of this invention may be prepared from a S-substituted-2,4-disulfamylaniline in a two step process which first involves a-haloacylation of the aniline compound to produce a 5-substituted-2,4-disulfarny-l (a-halo)acylan|ilide and then treatment of this product with an amine or ammonia. 5-substituted-2,4- disulfamy-l-(a-halo)acylanilide may be represented by the following formula:

SOzNHz wherein (a) A is selected from the group consisting of Cl, F, Br, N0 alkanoyl containing 2 to 4 carbon atoms, trifluoromethyl, and alkyl and alkoxy each containing from 1 to 3 carbon atoms;

(b) is selected from the group consisting of F, Cl, Br and I;

(0) R and R are selected from the group consisting of hydrogen, alkyl groups containing from 1 to 3 carbon atoms, phenyl and arkalkyl and aralkyl each containing from 7 to 8 carbon atoms.

As mentioned above, the carbon content of the alkanoyl and hydrocarbon substituents represents the preferred range. Substituents of higher carbon content may be employed but are not preferred for reasons as explained above. Representative compounds of this type are:

5chloro2,4-disulfamyl (a-chloro) acetanilide; S-bromo-2,4-disulfamyl (aachloro)acetanilide; 5-methoxy-2,4-disulfamyl (a-bromo propionanilide; 5-nitro-2,4-disulfamyl (oc-flllOIO, a-methyl)propion-anilide; 5- methyl-2,4-disul famyl (a-chloro)phenylacetanilide; 5-propoxy-2,4-disulfamyl (a-iodo, a-methyDphenylacetanilide; 5-c-hloro- 2, 4-sulfamyl (ct-chloro)-phenylpropionanilide; 5-chloro-2,4-disulfamyl (u-chloro)heptanoanilide; 5-propyl-2,4-disul famyl m-ChlOIO) phenylbutyranilide; 5-chloro-2,4-disulfamyl (wchloro)diphenylacetanilide; 5-bro-mo-2,4-disulfamyl (a-Ch'lOIO) (p-methylphenyl)- acetanilide; S-brom o-2,4-d isulfamy:l oL-Ch'lOl'O (p-ethylphenyl) acetanilide; 5-methyl-2,4-disulfarnyl oc-ChlOIO) acetanilide; 5-chloro-2,4-disulfamyl (oc-ChlOIO) acetanilide; 5-bromo-2,4-disul-famyl (oz-brOmO isobutyranilide; 5-chloro-Z,4-disulfamyl (a-chloro)valeranilide; 5 -chloro-2,4-disulfamy1 (a-chloro) phenylacetanilide; 5 -fluoro-2,4-disulfamyl a-chloro isobutyranilide; 5-acetyl-2,4-disulfamyl -(a-chloro)valeranilide; 5-trifluoromethyl-2,4-disulfa myl a-chloro acetanilide; 5-butyryl-2,4-disulfa myl (a-chloro) acetanilide; 5-fluoro-2,4-disulfamyl (a-chloro)acetanilide; 5-acetyl-2,4-disulfarnyl a-bromo) isobutyrani-lide; 5-iuoro-2,4disulfamyl (oc-bromo)acetanilide.

It has been surprisingly found that the above described 5-substituted-2,4-disulfamyl (a-halo)acylanilides are also highly efiective diuretic agents.

It has been unexpectedly found that these compounds may be prepared by the interaction of a selected (or-- halo) acid anhydride and a 5substituted-2,4-disulfamyl aniline in which the substituent is selected from the group consisting of chloro, fluoro, bromo, nitro, tr-ifiuoromethyl, alkanoyl containing 2 to 4 carbon atoms and alkoxy and alkyl each containing from 1 to 3 carbon atoms. The a halo acid anhydride may be represented by the following formula:

B O R1(|3-C| 0 12 1 wherein:

B is selected from the group consisting of fluoro, chloro, bromo and iodo, and R and R are selected from the group consisting of hydrogen, alkyl containing from 1 to 3 carbon atoms, phenyl and aralkyl and alkaryl each containing from 7 to 8 carbon atoms. For example, the above described 5-substituted-2,4-disulfamyl (a halo)acylanilides may each, respectively, be prepared by the interaction of the following pairs of reactants: chloracetic anhydride and 5-chloro-2,4disulfamyl aniline; chloracetic anhydride and 5-bromo-2,4-disulfamyl aniline; a-bromopropionic anhydride and 5-methoxy-2,4-disu1famyl aniline; a-fluoroisobutyric anhydride and S-nitro- 2,4-disulfamyl aniline; ot-chlorophenylacetic anhydride and S-methyl-ZA-disulfamyl aniline; a-iodo-or-methylphenylacetic anhydride and 5-propoxy-2,4-disulfamyl aniline; a-chlorophenylpropionic anhydride and 5-chloro- 2,4-disulfamyl aniline; a-chloroheptanoic anhydride and 5-chloro-2,4-disulfamyl aniline; a-chlorophenylbutyric anhydride and 5-propyl-2,4-disulfamyl aniline; :x-chlorodiphenylacetic anhydride and 5-chloro-2,4-disul-famyl aniline; a-ChlOIO (-p-methylphenyl)acetic anhydride and 5-bromo-2,4-disulfamyl aniline; 2-ch1oro (-p-ethylphenyl)acetic anhydride and 5-bromo-2,4-disulfa-myl aniline; chloracetic anhydride and S-methyl-ZA-disulfamyl aniline; S-chloro-2,4-disulfamylaniline and a-chloracetic anhydride; 5-bromo-2,4-disulfamylaniline and oc-ChlOIOiSObUtYIiC anhydride; 5-chloro-2,4-disulfamylaniline and a-chlorovaleric anhydride; 5-chloro-2,4-disulfamylaniline and a-chlorophenylacetic anhydride; 5 fluoro 2,4 disulfamylaniline and a-chloroisobutyric anhydride; S-acetyl-Z,4-disulfamylaniline and oc-ChlOlO- valeric anhydride; S-trifiuoromethyl-2,4-disulfamylaniline and a chloracetic anhydride; 5-butyryl-2,4-disulfamylaniline and a chloroacetic anhydride; 5-fluoro-2,4disulfamylaniline and a-chloroacetic anhydride; 5-acetyl-2,4- disulfamylaniline and a bromoisobutyric anhydride; S-fluoro 2,4-disulfamylaniline and a bromoacetic anhydride. Although the above described acylanilides may be prepared by reaction of the substituted aniline with (a halo)acylchlorides or (a halo)acid esters, it is preferable to employ the (a halo)acid anhydrides.

The reaction is generally effected by heating a mixture of the selected a halo acid anhydride with a 5-substituted 2,4-disulfamylaniline at a temperature of from about 60 to about 100 C. Usually a reaction time of from about 1 to about 4 hours is found to give excellent yield of the desired product. Heating for longer periods of time may result in decreased yield. Generally, a 1:1 molar ratio of the reactants may be employed. It is preferred to employ a large excess for example from 100 to 300% molar excess, of the selected acid anhydride. Intimate mixing of the reactants while heating is found particularly helpful, although not essential, since an excellent yield of the desired product is obtained. During the course of the reaction, it is at time found helpful to add a solvent, particularly if the reaction mixture should solidify, thus necessitating prolonged heating which may lead to reduced yield of the product. Liquid halogenated hydrocarbons, for example, chloroform, are found to be particularly suitable solvents. After the reaction is complete, the reaction mixture is treated with water to hyrdolyze unreacted anhydride. The solid residue is then recrystallized 6 from acetone to give the desired 5-substituted-2,4-disulfamyl (cc halo)acylanilide.

The above described 3,6-disubstituted-7-sulfamylbenzothiadiazine dioxides may be prepared by reacting a selected 5substituted-2,4-disulfamyl (0c halo)acylanilides with appropriate amines. For example, the above described substituted-benzothiadiazine dioxides may be prepared by reacting a 5-substituted-2,4-disulfamyl (a halo) acylanilide as described above with suitable amine, for example, where Y is a heterocyclic radical, such as piperidine, pyrrole, pyrrolidine and morpholine, where Y is ammonia, aliphatic amines such as methyl, dimethyl, dipropyl, ethylmethyl, methylpropyl and ethylpropyl amine; aromatic amines such as aniline, N-methylaniline; alkaryl amines such as o-toluidine, p-toluidine, p-ethylaniline and the various isomeric xylidines and aral kyl amines such as benzylamine and a and B phenylethylamine.

The above described 3,-disubstituted-7-sulfamy1- benzothiadiazine dioxides in which Z is a heterocyclic radical may be prepared by reacting a 5-substituted-2,4- disulfamyl (0c halo)acylanilide with an amine such as pyridine, pyrazine, thiazole, or pyrimidine.

The compounds in which Z is R1 N Rz or an N-alkylheterocyclic radical may be prepared by reacting a 5-substituted-2,4-disulfamyl (a-halo)acylanilide with a suitable tertiary amine such as trialkyl amines, for example, triethylamine, trimethylamine, tripropylamine, dimethylethylamine and diethylmethylamine; dialkylaryl amines, for example, dimethyl aniline, dimethyl-o-toluidine, diethyl-p-toluidine and methylethylaniline; alkyldiarylamines, for example, methyldiphenylamine and ethyldiphenylamine; N-alkyl, N-aralkyl, arylamines, for example, N-ethyl, N-benzylaniline and N-methyl, N-benzylaniline, or N-methylpiperidine, N- methylpyrrole, N-methylpyr-rolidine, N-ethylpiperidine, N-ethylpyrrolidine and so forth.

An alternative process for the preparation of the compounds in which Z is or an N-alkylheterocyclic ring is the treatment of the compounds in which Y is or a heterocyclic ring with lower alkyl halides or sulfate esters for example, alkyl chlorides, bromides and iodides or alkyl sulfates, to provide zwitter-ion compounds as exemplified in the above formula.

The process of preparing the above described 3,6-disubstituted-7-sulfamylbenzothiadiazine dioxides comprises heating a molar equivalent of the selected amine with a suitable S-substituted-2,4-disulfamyl- (a halo) acylanilide. Since hydrogen halide gas is a by-product of the reaction, a molar quantity of a hydrogen halide acceptor should be present in the reaction mixture. The hydrogen halide acceptor prevents consumption of the amine reagent part of which because of the formation of the amine hydrohalide would not react with the acylanilide. The hydrogen halide acceptor may be an alkaline reagent. By alkaline reagent as used in this disclosure is meant an oxide, hydroxide, carbonate or bicarbonate of an alkali metal, for example, sodium, potassium or lithium, or of an alkaline earth metal, for example, barium, calcium or magnesium. Alternatively, the selected amine reagent may be employed in a 2:1 molar ratio, in the absence of an alkaline reagent, the second mole of amine acting as the hydrogen halide acceptor.

It is preferred but not essential to use large excesses of the amine for best yields of the desired product. There appears to be no practical limit to the excess of amine to be employed, excellent yields being obtained when up to 1000% molar excess is employed. The large excesses of amine have further advantage in that they may also act as solvent for the reaction.

For best yields, the reaction is usually carried out at between from about 20 to about 120 C. for from about 1 to about 1-2 hours. Heating at higher temperatures and for longer periods of time may lead to reduced yield of the desired product. -It is preferred to use substantially anhydrous reagents although the presence of a minor amount of water does not seriously reduce the yield of product. It is often advantageous, but not necessary, to employ a solvent in the reaction, since the solvent permits a more intimate contact of the reactants. As mentioned above, the large excesses of the selected amine may act as solvent for the reaction. Dimethylformamide is also found to be a suitable reaction solvent.

After the reaction is complete, the product may be obtained by conventional methods. One such method involves the removal of excess amine at reduced pressure. The residue is then triturated with water, filtered and dried to obtain the crude product which may then be purified byrecrystallization methods. Water and acetone are found to be particularly suitable recrystallization solvents. The product may also be purified by dissolving in aqueous acid such as solutions of hydrohalic acid, e.g. hydrochloric acid and hydrobromic acid, sulfuric acid and so forth, and reprecipitation with alkali, for example, alkali metal carbonate, bicarbonate or hydroxide. The reprecipitated product is then filtered and dried.

The ideal diuretic agent should principally have an enhancing etfect on salt as well as water excretion. Additionally, it should maintain a sustained electrolyte balance of body fluids, for example, maintain normal pH values, normal potassium and bicarbonate levels and effect an equivalent excretion of sodium and chloride ions on a sustained basis. Further, a diuretic agent should have a continued eifectiveness during daily administration for protracted periods of time. Many diuretics of the prior art are limited in therapeutic application since they do not possess all of the above described properties. Some cause metabolic acidosis by increasing urinary pH; others cause increased potassium and bicarbonate ion elimination and no increase in chloride elimination. Many diuretics are not readily tolerated in prolonged therapy. Some diuretics initially possess many of these properties 'but on prolonged application either rapidly lose their desired effects or demonstrate a lack of continuous eifective action particularly in salt elimination. Because the use of these diuretics in therapy results in a number of undesirable efiects, they have only limited application since they may be used under only seriously restricted conditions. Generally, certain diuretics are used in combination with other diuretics so that the combination posses'ses an appreciable number of the above described prop er-ties.

The therapeutic agents of the present invention possess a number of the properties of an ideal diuretic which makes them valuable compounds for therapeutic application.

The therapeutic agents of this invention may be administered alone or in combination with pharmaceutically acceptable carriers, the proportion of which is determined by the solubility and chemical nature of the compound, chosen route of administration and standard pharmaceutical practice. For example, they may be administered orally in the form of tablets or capsules containing such excipients as starch, milk sugar, certain types of clay and so forth. They may be administered sublingually in the form of troches or lozenges in which the active ingredient is mixed with sugar and corn syrups, flavoring agents and dyes; and then dehydrated suificiently to make it suitable for pressing into a solid form. They may be administered orally in the form of solutions which may contain coloring and flavoring agents or they may be injected parenterally, that is intramuscularly, intraveneously or subcutaneously. For parenteral administration they may be used in the form of a sterile solution containing other solutes, for example, enough saline or glucose to make the solution isotonic.

The physician will determine the dosage of the present therapeutic agents which will be most suitable and it will vary with the form of administration and the particular compound chosen, and furthermore, it will vary with the particular patient under treatment. He will generally wish to initiate treatment with small dosages substantially less than the optimum dose of the compound and increase the dosage by small increments until the optimum eflect under the circumstances is reached. It will generally be found that when the composition is administered orally, larger quantities of the active agent will be required to produce the same effect as a smaller quantity given parenterally. The compounds are useful in the same manner as other diuretics and the dosage level is of the same order of magnitude as is generally employed with these other therapeutic agents. The therapeutic dosage will generally be from 500 to 2000 milligrams per day although it may be administered in several difierent dosage units. Tablets containing from 250 to 500 mg. of active agent are particularly useful.

In the foregoing, reference is made to pharmacologically acceptable anions and cations. Examples of a pharmacologically acceptable anion are iodide, chloride, bromide, sulfate, methylsulfate, acetate, propionate, tartrate, citrate, gluconate, and so forth. The term, pharmacologically acceptable anion has a definite meaning to one skilled in the art. It is defined as non-toxic anion of any of the simple acids commonly used in pharmacology to neutralize basic medicinal agents when the salt thereof is to be used therapeutically. The pharmacological activity of the molecule is primarily a function of the cation, the anion serving chiefly to supply electrical neutrality. Pharmacologically acceptable cations also has a definite meaning to one skilled in the art. It is defined as a non-toxic cation of basic compounds commonly used in pharmacology to neutralize acid medicinal agents when the salt thereof is to be used therapeutically. The pharmacological activity of the molecule is primarily a function of the anion, the cation serving chiefly to supply electrical neutrality. Commonly employed pharmacologically acceptable cations are, for example, sodium, potassium, calcium, and magnesium. These acid and base addition salts of the compounds of the present invention may be prepared employing. conventional procedures. One such procedure involves treating the subject compounds with an aqueous solution containing an equivalent amount of the reagents, i.e. the pharmacologically acceptable base, followed by concentration of the resultant mixture to obtain the desired product. Pharmacologically acceptable acids are those which contain the anions described above. Pharmacologically acceptable bases are those which contain the cations described above. Such bases may be, for example, oxides, hydroxides, carbonates or bicarbonates.

The above described '5-substituted-2,4-disulfamylanilines may be prepared by procedures described in the literature, tor example, the general procedure described in Monatsh. Chem. vol. 48, p. 87 (1927) which involves the treatment of a meta-substituted aniline with from 10 to 20 parts by weight of chlorosulfonic acid followed by the gradual addition of from about 90 to 170 parts by weight of sodiumv chloride. The resultant mixture is heated at approximately C. for about 2 hours after 9 which the reaction mixture is poured into water and the resultant S-substituted aniline-2,4-disulfonyl chloride is filtered and is then treated with concentrated ammonium hydroxide by standard procedures to obtain the corre- 10 then added and heating was continued for a total of 3 hours. The mixture was then cooled, filtered and washed with chloroform. The solid residue was then tritur-ated with 50 ml. of water, filtered and then recrystallized sponding disulfonamide. The meta-substituted anilines, trom acetone after treatment of the hot acetone solution for example, meta-chloro, meta-fiuoro, meta-bromo, with activated carbon. Eight grams of 5-methyl-2,4-dimeta-nitro, meta-alkanoyl, meta-alkyl, meta-trifluorosulfamyl (a chloro)acetanilide, M. 222 223 C. (d.), methyl and meta-alkoxy anilines, may be readily obained was obtained. Elemental analysis of the product agreed or prepared by standard procedures known to one skilled with the calculated values. in the art. The u-haloacid anhydride may be prepared by conventional procedures, for example, heating the corre- EXAMPLES HI X H sponding a-haloacid in excess acetic anhydride, followed A number of 5-substituted-2,4-disulfamyl (a halo)- by removal of the acetic anhydride-acetic acid mixture so acylanilides were prepared according to the procedures formed leaving the desired a-haloacid anhydride. The described in Examples I and II. The experimental data above procedure is commonly employed in the art. is summarized in Table I in which is given the products Alternatively, the anhydride may be prepared by sublnnaand reactant-s (substituted anilines and a halo acid antion in vacuo of the corresponding a-haloacid. Further, hydrides).

Table I Reaction 5-subst1tuted-2,4-disulfamy1 5-substrtuent of Molar (a halo) acylanilide 5-substituted2,4-di- (a halo) acid anhydride Ratio sultamyl aniline Temp. Time 0.) (hrs.)

5-bromo-2,4-disultamyl (a bromo a chloroacetic anhydride 4:1 100 /z chloro) acetanilide. 5-methoxy-2,4-disulfamy1 (a methoxy a bromopropionic anhydride--. 2:1 100 2 bromo) propionanilide. 5-nitro-2A-disulfamyl (a fluoro, nitro a fluoroisobutyric anhydride.--" 3:1 60 3 a methyl) propionanilide. 5-methyl-2,4-disu1farnyl (a methyl (a chloro) pheuylacetic anhy- 1:1 100 3 chloro) phenylacetanilide. dride. VII 5-propoxy-2,4-disu1famyl (a propoxy (a iodo) (a methyl) phenylacetic 1:1 100 3 ipio, a methyD'phenylacetamanhydride.

1 6. VIII 5-chloro-2,4-disulfamyl (a chloro (a chloro) phenylpropionic 1:1 100 3 chloro) phenylpropionanhydride. anilide. IX 5-chloro-2,4-d1sulfamyl (a do a chlorobutyric anhydride 3:1 60 3 chloro) butyroanilide. X 5-propyl-2,4-disuliamy1 a propyl (a chloro) phenylbutyric anhy- 2:1 100 chloro) phenylbutyranihde. dride. XI 5-chloro-2,4-disulfamyl (o: chloro (a chloro) diphenylacetic anhy- 2:1 100 1 chloro)diphenylacetanilide. dride. XII 5-bromo-2,4-disulfamyl (a bromo (a chloro)-p-methylphenyl 1:1 100 3 chloro) (-p-methy1phenyl) acetic anhydride. acetanilide. XIII 5-bromo-2A-(a chlqr0)(-p-ethyld0 (a chloro)-p-ethylphenyl acetic 1:1 100 3 phenyl) acetanihde. anhydride. XIV 5-ch1oro-2,4-disulfamyl (a chloro a chloroacetic anhydride 4:1 60 3 chloro) acetanilide. XV 5-bromo-2,4-disu1famyl (a bromo a chloroisobutyric anhydride.-. 3:1 100 bromo) ,isobutyranilide. XVI 5-chloro-2,4-disulfamyl (a 0111010 a chlorovaleric anhydride 3:1 60 2 chloro) valeranilide. XVII 5-chloro-2,4-disulfamyl (0; do (a chloro) phenyl-acetic anhy- 2:1 100 2 chloro) phenylacetamhde. dride.

NOTE.II1 Table I, Molar Ratio refers to molar ratio of anhydride to aniline compou nd.

such anhydrides may be prepared by the interaction of the sodium salt of the selected a-haloacid and the corresponding u-haloacylhalide, a well-known procedure.

The following examples are given by Way of illustration and are not to be construed as limitations of this invention many variations of which are possible within the scope and spirit thereof.

EXAMPLE I A mixture of 2 g. (0.007 mole) of 5-chloro-2,4-disulfamylaniline and 5.0 g. (0.029 mole) of a chloroa'cetic anhydride was heated with stirring at 100 C. for two hours. The solid reaction mixture was then tritu-rated in 50 ml. of water after which the mixture was filtered, washed with water and dried to obtain 2.1 g. of S-chloro- 2,4-disult'amyl (a chloro)acetanilide. The product was recrystallized from acetone-ether to obtain a pure sample, M. 360 C. Elemental analysis gave the following results:

Calculated for: C H O N Cl S C, 26.53; H, 2.50; N, 11.60. Found: C, 26.41; H, 2.51; N, 11.90.

EXAMPLE II A mixture of 9.3 g. (0.035 mole) of 5 methyl-2,4-disulfamyl aniline and g. (0.15 mole) of u chloroacetic anhydride was heated at 60 C. After 15 minutes the mixture solidified. Fifty milliliters of chloroform were EXAMPLE XVIII A mixture of 7.3 g. (0.024 mole) of 5 chloro-2,4-disulfamyl (a chloro) acetanilide and 34.4 g. (0.40 mole) of piperidine was heated with stirring at C. for 2 hours. The excess piperidine was removed at reduced pressure and the solid residue triturated with water. The solid mixture was dissolved in an equivalent amount of 10% hydrochloric acid, the resultant solution treated with activated carbon and filtered. The resultant solution was adjusted to pH of about 8.0 with sodium bicarbonate where the product precipitated. After washing and drying, the product was recrystallized from acetone to obtain pure 3 (N piperidinomethyl) 6 chloro 7 sulfamylbenzothiadiazine dioxide, M. 267-2675 C. Elemental analysis gave the following results:

Calculated for: C13H17O4N4S2C1I C, 39.74; H, 4.36; N, 14.26. Found: C, 39.97; H, 4.48; N, 14.08.

EXAMPLE XIX A mixture of 2.73 g. (0.008 mole) of 5-methyl-2,4-d-isulfamyl (a chloro) acetanilide, 6.4 g. (0.08 mole) of piperidine and '10 ml. of dimethylformamide was allowed to stand at room temperature for 12. hours. Dimethyltormamide was stripped at reduced pressure, leaving a gummy oil which was treated with 50 ml. of water. The

' residue was then treated with a solution of sodium bicarbonate until all the solid dissolved. The solution was zine dioxides in which Y is or a heterocyclic radical were prepared according to the procedures described in Examples XVIII to XXI. The experimental data is summarized in Table II.

Table II 3,6-disubstituted-7-sulfamyl benzothier Reactants diazine dioxide (i-substituent 3-substituent Amine Acylam'lide XXII bromo N-pyrrylmethyl pyrrole 5-bromo-2,4-disulfamyl(a 5:1 80 2 chloro) acetanilide. XXIII methoxy a-N-pyrollidino-a-ethyL pyrrolidine 5-Iuethoxy-2,4-disulfamyl 10:1 120 l (a-brommpropionanilide. XXIV methyl a-N-morpholino-a-benzyL- morpholine 5-methyl-2,4-disulfamyl(or 2:1 100 4 chloro) phenylaeetauilide. XXV chloro BN-piperidino-B-phenylpiperidine 5-chloro-2,4-disulfarnyl (a 10:1 80 2 ethyl. chloro) phenylpropionanilide. XXVI methoxy a-N-piperidino-a-ethyl "do 5- et Xy-2,4-dlsu1iamyl(a :1 100 3 bromo) propionanilide. XXVII nitro 2-N-piperldino-2-propyl d0 5-11ltr0-2,4-disulfamy1(a 5:1 120 1 fluoro, a methyl) propionanilide. XXVIII propoxy a-N-pyrrolidino-wphenylpyrrolidine 5-pr0poxy-2,4-disulfamyl (a 2:1 80 4 ethyl. 10110, a methyDphenylacetanilide. XXIX nitro Z-N-methylamino-Z-propyl. methylamine 5-11itr0-2,4- is 1famy1(a :1 4

fiuoro, or methyl) propionanilide. XXX propoxy a-N-propylamino-a-phenylpropylamine 5-propoxy-2,4-dlsulfamyl 10:1 80 1 ethyl. (a iodo, a methyl) phenylacetanilide. XXXI chloro a-N-anllino-q-butyl aniline 5-chl0r0-2,4-disulfamyl (or 5:1 120 1 ehloro) butyro anilide. XXXII propyl y-N-o-toluidinow-phenylo-toluidine 5-propyl-2,4-disulfamyl (a 1:1 120 3 propyl. chlilrrg) phenylbutyrarui e. XXXI11 chloro N-ethyl-N-methylamino ethylmethyl- 5-0hl0ro-2,4-disulfamyl(a 5:1 100 4 (diphenyl) methyl. amine. 01113313) diphenylaceta 1 e. XXXIV bromo a-N,N-dipropylamino-adipropylamlne 5-bromo 2,4-disulfamyl (0: 10:1 100 2 p-methylbenzyl. chloro) (p-methyphenyl) aeetam'llde. XXXV do a-N,N-dimethylamino-adimethylamine. 5-br0m0-2,4-disulfamyl (a 5:1 80 1 p-ethylbenzyl. chloro) (p-ethylphenyl) acetanihde. XXXVI chloro N-benzylaminomethyl benzylamine 5-chloro-2,4-disulfamyl(a 5:0 90 2 chloro) aeetanilide. XXXVIIu nitro 2-N-phenylethylamino-2- phenylethyl- 5-nitro-2,4-disulfamyl (a 1:1 120 4 propyl. amine. fiupfig, a methyl) propionam e. XXXVIII methoxy a-N-p-toluldino-a-ethyl. p-toluidine 5-methoxy-2,4-disulfamyl(a 4:1 100 3 bromo) propionanilide. XXXIX- methyl N-mcthylanilinomethyl-- N-methylaniline 5'methyl-2A-disulfamy1m 2:1 20 12 chloro) acetanllide. XL bromo 2amino-2-propyl ammonia 5-br0mo-2,4-disulfamyl(a 5:1 20 8 chloro) isobutyranilide. XLI chloro l-amino-l-butyl... 10 5-ch10r0-2,4-disullamyl(a 10:1 20 4 chloro) valeranilide. XLII do a-aminobenzyl d0 5-chloro-2,4-dis11lfamyl (a 10:1 10 12 chloro) phenylaeetanilide.

In Table II:

A" is the molar ratio of amine to acylanillde.

B is the reaction temperature.

C is the reaction time.

by cooling the hot solution after adding ml. of concentrated hydrochloric acid. The purified product melted at 293 294 C. (d.). Elemental analysis gave results which agree with the theoretical values.

EXAMPLE XX A mixture of 3.6 g. (0.01 mole) of S-chloro-ZA-disulfamyl (a chloro) acetanilide in 10 ml. of concentrated NH OH was allowed to stand at 20 C. for 8 hours. The mixture was evaporated under reduced pressure to obtain crude product which was recrystallized from acetone to give pure 3-(aminornethyl)-6-ch1oro-7-sulfamylbenzothiadi-azine dioxide.

EXAMPLE XXI The procedure of Example XIX, employing 0.008 mole of piperidine in the presence of an equimolar amount of sodium bicarbonate with comparable results.

EXAMPLES XXII-XLII A number of 3,6-disubstituted-7-sulfamylbenzothiadia- EXAMPLE XLIII EXAMPLE XLIV A mixture of 2.73 g. (0.008 mole) of 5-methyl-2,4- disulfamyl (a chloro) acetanilide and 6.3 g. (0.08 mole) of pyridine in 10 ml. of dirnethylformamide was heated at C. for one hour. The reaction mixture was cooled in ice and diluted with a 1% solution of sodium bicarbonate. The crude product separated, was filtered, washed with water and dried. The crude product was suspended in water and 40% NaOH solution was added to clear the solution. Carbon dioxide gas was passed into the solution to precipitate 3-(N-vpyridiniummethyl)-6-methyl- 14 EXAMPLE LXIV One mole of a chloro phenylacetic acid was refluxed with one mole of acetic anhydride. After 3 hours, the resultant acetic anhydride-acetic acid mixture Was re- 7-sulfamylbenzothiadiazine dioxide which was filtered, Washed i water and dried 252 g) 2g7 2 3 moved by distillation at reduced pressure. The residue was crude a. chloro phenylacetic anhydride which was XA XLV then purified by recrystallization from benzene.

In the same manner, other at chloro acid anhydrides procedure of Example X11111 was repeated the employed in the above examples were prepared. addition of 0.004 mole of potassium carbonate with cornparable results. EXAMPLE LXV EXAMPLES XLVLLH The hydrochloride of 3-(N-piperidinomethyl)-6-chloro- A number of 3,6-disubstituted-7-sulfamylbenzothiadia- 7-sulfamylbenzothiadiazine dioxide was prepared by diszine dioxides in which Z is a heterocyclic radical were solving this compound in an aqueous solution containing prepared by the procedures described in Examples XLII an equivalent molar amount of hydrochloric acid. The to XLIV. The experimental data is summarized in Table solution was then concentrated under reduced pressure III. to obtain the hydrochloride. This procedure was repeated Table III 3, fi'disubstituted-Tsulfamylbenzothiadia- Reactants zine dioxides 3-substituent 6-substituent Amine Aeylanilide XLVI pyrazinium-methyl bromo pyrazine 5-bromo-2,4-disulfamyl(a 10:1 100 2 chloro) acetanilide. XLVII l-N-thlazolium-l-ethyl meth0xy thiazine 5-methoxy-2,4-disulfamyi 5:1 80 4 (a bromo) propionenilide. XLVIII 2-N-pyridinium-2-propyL-.. nitro pyridine 5-nitro-2,4-disuliamyl (a 5:1 8

fluoro, a methyl) propionanilide. XLIX a-N-thiazolium-a-phenylpr0p0xy thiazole 5-prop0xy-2,4disulfamyl (a 2:1 120 4 ethyl. iodo, amethyl) phenylacetanilide. L N-pyrimidinium-methylm ehloro pyrimidine 5-chloro-2,4-disulfamyl (a 10:1 100 2 chloro) aeetanilide. LI a-N-pyridinium-a phenylprop0xy pyridine 5-prop0xy-2,4-disulfamy1(a 2:1 20 10 ethyl.) iodo, a methyl) phenylacetanilide. LII N-tl1iazolium-methyl chloro thiazole 5-chloro-2,4-disnlfamyl (a 10:1 100 2 chloro) acetanilide.

EXAMPLES LIII TO LXIII employing a solution of hydrogen chloride in ethyl alco- 3,6-disu-bstituted-7-sulfamylbenzothiadiazine dioxides in ho} w comparable results which Zis ThlS procedure was employed or the preparation of other acid addition salts, i.e. the hydrobromide, hydriodide and sulfate. N-RZ EXAMPLE LXVI R1 7 The potassium salt of 3-(N-piperidiriomethyl) 6-methor an N-alkylheterocyclic radical were prepared employyl-7-sulfamylbenzotbiadiazine dioxide was prepared by ing the procedures described in Examples XVIII to XXI. dissolving the compound in an aqueous solution, contain- The experimental data are tabulated in Table IV: ing an equivalent molar amount of potassium carbonate.

Table IV 3, G-disubstituted-7-sulfamylbenzothiadia- Reaetants zine dioxides A B C 3-substituent fi-substituent Amine Acylanilide LIII N-methylpiperldinomethylehloro N-methylpiperi- 5chl0ro-2,4-disulfamyl(a 4:1 3

dine. chloro) acetanilidc. LIV N-methylpyrrylmethyl-- bromo N-methylpyraz- 5-br0m0-2,4-disulfa1ny1(a 2:1 20 12 inc. chloro) aeetanilide. LV 2N,N,N-trimethylaminonitro trimethylamine 5-nitr0-2,4-disu1famyl (a 10:1 20 8 Z-propyl. fiu irg, amethyl) propion- Q11! 1 e. LVI N,N,N,-triethylaminochloro .do 5-chloro-2,4-disu1famy1(a 5:1 100 3 methyl. chloro) acetanllide. LVII N,N,N-tripropy1aminodo tripropylamine- 5-eh1oro-2,4-disulfamyl (a 5:1 100 3 methyl. chloro) acetanilide. LVIII N,N,Ntriethylaminomethyl triethylamine 5-methyl-2,4-disu1famyl(a 5:1 100 2 methyl. chloro) aeetanilide. a-N-methylpyrrolidino-ameth0xy N-methylpyrroli- 5-methoxy-2,4-disulfamy1(a 4:1 100 3 ethyl. dine. bromo) propionanilide. N-methylpyrrylmethylbromo N-methylpyrazfi-bromdZA-disulfimyl (a 2:1 2

ine. chloro) acetanilide. a-N,N-dimethyl p. methoxy N,N-di1nethyl-p. 5-methoxy-2,4-disulfamyl 4:1 100 3 toluidino-a-ethyl. toluidine. (a bromo) propionanilide. N,N-diethyl,N-benzylchloro NN-diethyl- &chloro-2,4-disulfamyl (a 5:1 100 4 aminomethyl. enzylamine. chloro) acetanilide. a-N,N-dimethylanilino-ado N-N,dimethyl- 5-ehl0ro-2,4-disulfamy1(a 5:1 100 4 butyl. aniline. chloro) valeranilide.

EXAMPLE LXVII The hydrochloride of 3-(N-piperidinomethyl)-6-chloro- 7-sulfamylbenzothiadiazine dioxide was dissolved in water to which was then added an equivalent molar amount of silver acetate. The silver chloride precipitate which formed was filtered and the filtrate evaporated to obtain 1 6 EXAMPLE LXX Into the tablet base of Example LVIII there is incorporated a suflicient amount of 3-(N-piperidinomethyl)-6- ch10ro-7-sulfamylbenzothiadiazine dioxide hydrochloride to provide tablets each containing 0.5 g. of active ingredient.

EXAMPLES LXXILXXVII Additional 5-substituted-2,4-disulfiaimyl (a halo)acylanilides were prepared according to the procedures described in Examples I and II. The experimental data are given in Table V.

Table V Reaction 5-substituted-2,4-disulfamyl 5-substituent of Molar (a halo) acylanilide 5-substituted-2,4-di- (a halo) acid anhydride Ratio suli'amyl aniline Temp. Time 0.) (hrs) LXXI 5-fluoro-2,4-disuifamy1 fiuoro a chloro isobutyric anhydride 3:1 100 1 (a chloro)-isobutyranilide.

LXXII 5-acety1-2A-gisultamyi (a chloro) a chioro-valeric anhydnde 2:1 100 3 valeranili e.

LXXIII 5-trifiuoro-methyl-2,4disuliamyi trifiuoro-methyl c: ehloro-aeetic anhydride 4:1 60 2 (a chloro) acetanilide.

LXXIV. 5-bntyryl-2,4-disulfamyl (a butyryl ..d 4:1 60 2 chloro) acetanilide.

LXXV- -fluor0-2,4-disulfamyl (a chloro) fiuoro d0 3: 1 100 2 acetanilide.

LXXVL... fi-acetyl-2A-disuifamyi (a acetyl a bromo-isobutyric anhydnde..- 3:1 100 2 bromo) isobutyraniiide.

LXXVII. ofluoro'lqrdisulfamyi (a flnoro a bromo-acetic anhydride 4:1 100 1 bromo) acetanilide.

the acetic acid addition salt of 3-(N-piperidinomethyl)-6- chioro-7-sulfamylbenzothiadiazine dioxide.

In a similar manner, the tartaric, citric, gluoonic and propionic acid addition salts were prepared.

EXAMPLES LXXVIII TO LXXXVI Additional 3,6-disubstituted-7-sul-famylbenzothiadiazine dioxides were prepared according to the above described procedures. The experimental data are given in Table VI.

Table VI 3,6-dlsubstituted-7-su1iamylbenzothiadia- Reactants zine dioxides A B O 3-substituent 6-substituent Amine Acylanilide LXXVIII 2-amino-2-propyl fiuoro ammonia 5-fiuoro-2,4-disulfamyl (a :1 4

chloro) isobutyranllide. LXXIX- l-amino-l-butyL. acetyl fi-acetyl-ZA-disull'amyl (a 10:1 20 4 chloro) valeranilide. LXXX aminomethyl trifiuoro- 5-trifluorornethyl-2,4-disuli- 10:1 20 12 methyl. inlyl (a chloro) acetani- 1 e. LXXXI do butyryl do 5-butyryl-2,4-disuliamyl(a 10:1 20 8 chloro) acetanilide. LXXXIL... 2-amino-2-propyl acetyl do 5-acety1-2,4-disuitamyl (a 10:1 20 12 bromo) isobutyranilide. LXXXIII. N-piperldinomethyl piperidine 5-fluoro-2,4-disu1iarnyl(a 4:1 100 3 chloro) aeetanilide. LXXXIV. 2-N-pyrryl-2-propyl pyrrole 5-fluoro-2,4-disulfamy1(a 5:1 20 8 chloro) isobutyranilide. LXXXV pyridine 5-fiuoro-2,4-disulfamyl (a 5:1 20 s bromo) acetanilide. LXXXVI .do trlfluorodo 5-triiiuoro'2,4-disulfamyl(a 10:1 100 2 methyl chloro) aeetanilide.

EXAMPLE LXVIII A tablet base is prepared by blending the following ingredients in the proportion by weight indicated:

Sucrose U.S.P. 82.0 Tapioca starch 13.6 Magnesium stearate 4.4

Into this base there is blended a sufiicient amount of 3- (N piperidinomethy-l) 6 chloro 7 sulfamylbenzothiadiazine dioxide to provide tablets containing 250 mg. of active ingredient.

EXAMPLE LX-IX Into the tablet base of Example LVIII there is blended a sufiicient amount of 3-(N-piperidinomethyl)-6 methyl- 7-sulfarnylbenzothiadiazine dioxide to provide tablets containing 0.5 g. of active ingredient.

17 wherein:

(a) A is selected from the group consisting of Cl, r, Br, N trifluoromethyl, alkanoyl having from 2 to 4 carbon atoms and alkyl and alkoxy each having from 1 to 3 carbon atoms;

(b) R and R are selected from the group consisting of hydrogen, alkyl having from 1 to 3 carbon atoms, phenyl and aralkyl and alkaryl each having from 7 to 8 carbon atoms;

(c) Y is selected from the group consisting of piperidino, pyrryl, pyrrolidino, morpholino and in Which R and R are as defined above; and

(d) Z is selected from the group consisting of pyridinium, pyrazinium, pyrimidinium, thiazolium, N- alkylpiperidino, N-al-kylpyrryl, N-al-kylmorpholino, N-alkylpyrrolidino, the N-alkyl of each having from 1 to 3 carbon atoms, and

in which R and R are as defined above and R is alkyl having from 1 to 3 carbon atoms.

2. A compound of the formula:

N lower alkyl X CIAN 112N028 /NH lower alkyl References Cited in the file of this patent UNITED STATES PATENTS 2,117,260 Stuart May 10, 193 8 2,169,971 Behnisch Aug. 15, 1939 2,289,029 Mietzsch et al July 7, 1942 2,809,194 Novello Oct. 8, 1957 2,910,476 Novello Oct. 27, 1959 OTHER REFERENCES Chemical Abstracts, vol. 46, The Naming and Indexing of Chemical Compounds (1953), pages 12413-12417, call N0. QD 7C4 (1953).

Novel'lo et a1.: Jour. Am. Chem. Soc., vol. 79, Apr. 1957, pages 2028-29.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3,110,716 November 12, 1963 William M. McLamore et 211.

It is certified that error appears in the above identified patent and that said Letters Patent are hereby corrected as shown below:

lines 70 to 75, change the single bond Column 16,

double bond.

between the 3- and 4-positions to a Signed and sealed this 11th day of November 1969.

(SEAL) Attest:

WILLIAM E. SCHUYLER, JR.

Attesting Officer 

1. THE AMPHOERIC COMPOUND AND THE PHARMACOLOGICALLY ACCEPTABLE ACID AND BASE ADDITION SALTS THEREOF, SAID COMPOUND BEING SELECTED FROM THE GROUP REPRESENTED BY THE FORMULAE: 